Rheumatoid arthritis (RA) is a systemic inflammatory disease which causes mainly in the arthrosynovia. Today Methotrexate (MTX) is used generally as disease-modified anti-rheumatic drugs (DMARD), but the efficacy for inflammatory responses or arthritis mutilans is not enough. On the other hand, the biologics, which targeted cytokines (TNF, IL-1, IL-6), has been revealed recently its efficacy for RA, and it has been proved the importance of these cytokines in the manifestation of RA. In particular, the monoclonal TNF antibody Remicade and soluble TNF receptor fusion protein Enbrel, which inhibit the TNF function, are worthy of note because of the unprecedented efficacy not only for inflammatory response but for arthritis mutilans.
Though the fact above suggests importance of the treatment for RA in future, these biologics have fundamental drawbacks related to patient cost, efficacy of production, limitation of administration to hypodermal or intravenous injection, and so on. So, the anti-RA drugs in the next generation are expected to overcome these problems, that is to be an orally small-molecule drug, which blocks or modulates selectively the function of these cytokines. In particular p38α mitogen activated protein kinase (p38α MAPK) belongs to intracellular phosphorylation kinase participating in production and/or functional expression of the cytokine (TNF, IL-1, IL-6), and it is reported that p38α MAPK is activated in the arthrosynovia of RA patients thereby cytokines are produced excessively, so that p38α MAPK has been attracted as a target of anti-RA drug.
These anti-inflammatory agents or compounds having cytokine inhibitory activity have been described (WO98/22457, WO00/41698, WO00/43384, WO01/22965, WO02/07772, WO02/58695, WO03/041644, etc.) but pyridone derivatives having these activities are only described in WO2006/051826, WO2006/122154, WO2007/040208, WO2007/053610, WO2007053685, which does not include the compounds of the present invention, as far as we know.